Stem cells opening path to brain repair

After 10 years, the drugs Dr. Jacqueline Winterkorn had been taking to quell the shaking and immobility of Parkinson's disease were wearing off.

"It's a very sad disease," she said. "People are locked into bodies that don't move. Their brains are working, their minds are working, but they can't talk and they can't move."

That changed a year and a half ago when Winterkorn was given millions of new fetal brain cells to replace those that were supposed to be producing dopamine to control her movements but instead were dying off.

The new cells took up residence in her brain, extending delicate tendrils to motor neuron cells, supplying them once again with dopamine.

This is not a cure, Winterkorn, who lives in Roxbury, Conn., is quick to say. But she estimates the brain tissue transplant improved her mobility by about 30 percent.

Winterkorn and a handful of other pioneers who are receiving brain cell transplants to repair the damage from Parkinson's disease, stroke, Huntington's disease and epilepsy are providing important new evidence that the brain may be a lot easier to repair than previously thought.

"The prospect of repairing a damaged brain is pretty remarkable," said Dr. Curt Freed of the University of Colorado Health Sciences Center in Denver, who headed the just-completed Parkinson's transplant study.

"It has been possible to show significant improvements in some patients who suffered from a chronic neurologic disease for an average of 14 years."

New research is overturning old notions about how the brain works. Once thought to be unchangeable, unrepairable and constantly losing neurons, the brain is now seen to be always changing, eminently repairable and constantly making new cells.

One of the new findings, which has enormous implications, involves brain stem cells, a newly discovered cell line that has the almost magical ability to make every other type of brain cell, including more of itself.

Preliminary experiments in animals suggest it may be possible to inject brain stem cells into patients with a wide range of mental disorders to cure diseases such as Alzheimer's disease and multiple sclerosis.

The first results in mice show that mouse brain stem cells find their way to areas of the brain with damaged cells like millions of Tarzans swinging through a jungle of trees, make healthy copies of the wrecked cells and correct the disorder, in this case an animal model of multiple sclerosis.

Scientists don't know how stem cells do this, but they believe that the brain and the stem cells talk to each other using a chemical language.

In a sense, stem cells ask every cell they encounter "Are you OK?" If not, they pop out a healthy cell to take over the job of the sick one.

"A few years ago people looked at the adult brain and saw it in a very static way," said Dr. Ronald McKay, chief of molecular biology at the National Institute of Neurological Disorders and Stroke.

"Now we know it's a very dynamic structure," he said. "The way the brain works is controlled by signals that are passed between cells. It gives us much more hope that we can understand these signals and use that understanding to control the diseases of the nervous system."

If transplanted stem cells work as well in humans, then replacing errant brain cells with normal ones raises the possibility of fixing an entirely different class of mental disorders, from schizophrenia to depression.

"This is a dramatic new way of looking at both the development and repair of the brain," said Dr. Evan Snyder of Harvard Medical School and Children's Hospital in Boston, who reported isolating human brain stem cells from fetal tissue last November.

"There's a whole new class of brain diseases that can now be approached that couldn't before," he said.

Another new finding indicates that the brain may be able to regenerate itself like the liver.

Instead of losing copious amounts of brain cells with age, human brains may be doing just the opposite, making thousands of new ones every day.

This possibility is based on research showing that adult rats continually make new cells in the hippocampus, an area of the brain important for learning and memory. In an earlier report, Fred Gage of the University of California at San Diego found that adult humans also make new hippocampal cells.

The trick to keeping these new cells is a type of learning that requires making associations that are separated either in time or space.

Rats given new tasks to learn make use of the newly made brain cells, incorporating them as permanent structures in the brain. Rats that do not experience learning lose the newly minted cells.

"The fact that learning specifically rescues these new cells from death suggests that they are important for learning, and not just that they are affected by learning," said neurobiologist Elizabeth Gould of Princeton University, who has so far found the overproduction of new brain cells in rat and monkey hippocampuses.

The ability of the brain to make loads of new brain cells in the hippocampus opens the door to brain self-repair, especially if other areas of the brain also generate fresh cells. The key is learning how to turn up an individual's own stem cell production to replace defective neurons.

"I think we can use this naturally occurring regeneration to devise strategies for repairing damaged brain regions," Gould said.

Enhancing the brain's own recuperative powers could ease the controversy over the use of human fetal brain cells, which are obtained from aborted fetuses. The National Institutes of Health has lifted its ban on the use of human fetal cells and is funding a number of studies involving their use.

While human trials using stem cell transplants, or the brain's own regenerative capacity, may still be years away, fetal transplants for Parkinson's disease and other neurological problems involving localized damage appear to be on the horizon.

The partial success experienced by Winterkorn resulted from a double-blind, placebo controlled study involving 40 patients. Half received fetal cells and the other half went through the surgery and skull-drilling but did not receive new dopamine-producing cells.

"A double-blind study is unusual in surgery, but it's the only way to prove a treatment has an effect or not," Winterkorn said.

Freed, who headed the study, said a third of the patients who received fetal cells did extremely well, a third had some benefit, and a third either stayed the same or got worse.

After the study was over and the results announced, almost all of the patients who served as controls--who had the surgery but did not receive fetal cells--opted to get the cells in a second round of surgery.

Patients under 60 who received fetal cells did the best, while those older than 60 showed less improvement. Nevertheless, PET brain images showed that the transplanted cells grew in the brains of younger and older patients.

"That's a very interesting finding, that even if you're 70-plus years old a fetal dopamine cell transplant can survive, grow and develop in your brain," Freed said.

The next step is to see if the overall graft survival rate can be significantly increased, particularly in older patients, by bathing the fetal cells in growth factors, he said. Animal experiments show that such growth factors as FGF and IGF-1, which normally promote brain health and development, increase the transplant success rate, he added.

"There's growing optimism that fetal tissue transplants for Parkinson's disease will work," said Dr. Jeffrey Kordower, a Rush-Presbyterian-St. Luke's medical center neurologist, who is participating in a second transplant study for Parkinson's patients.

Kordower's autopsy studies of brain tissue from two patients who had received fetal cell, but died from unrelated causes, showed that the fetal cells had taken root.

"The cells made connections with the host," he explained. "They did great. And the patients had done well, they had improved."

Similar results have been achieved in stroke patients. At the University of Pittsburgh Medical Center, neurosurgeon Dr. Douglas Kondziolka implanted adult neurons into the brains of 12 patients who suffered strokes as long as six years ago.

Preliminary results indicate that eight patients reported improvements in such capacities as speech, memory and muscle control. These patients suffered strokes in an area of the brain called the basal ganglia, which serves as a switching center for incoming and outgoing messages.

"We think that the improvement is related to cells hooking up with existing cells that did not die in the stroke and are now providing a better infrastructure for brain function," Kondziolka said.

The implanted neurons, which are commercially available, are derived from an unusual 25-year-old tumor that can be made to produce mature human brain cells. Once they become mature, they no longer are cancerous.

Transplants of fetal tissue and mature neurons may provide local brain repairs, but stem cells offer the opportunity to perform total brain repairs, such as for diseases like Alzheimer's where vast portions of the brain are eaten away, McKay said.

"It's fair to say that stem cells represent a breakthrough because of their remarkable properties," he said. "Stem cells will move long distances, and large numbers of them will incorporate into the brain. It's as if the brain is not a solid barrier. Stem cells can move through it."

As they move through the brain, stem cells look for damaged or inoperative cells and stop to make healthy copies. Snyder's studies with shiverer mice--so-called because they have a neurodegenerative disorder that causes them to shiver and die young-- revealed that injected stem cells locate the trouble, mutated oligodendrocytes, which are supposed to make myelin to insulate neurons.

Snyder isolated stem cells from a mouse 13 years ago without knowing what they were at the time. Only after years of research showed that these cells could make all the other cells in the brain were they declared to be stem cells.

Injected into the brains of shiverer mice, stem cells swung from cell to cell, pausing at the dysfunctional oligodendrocytes to make good copies.

"Stem cells are very opportunistic," Snyder said. "They love to migrate by themselves or on anything that has a surface."

Stem cells did their job in the shiverer mice. Myelin production started up. As insulation grew around neurons, shivering slowed and often stopped. Sixty percent of the treated animals improved, and some of them appeared to be completely normal.

Injecting the newly discovered human stem cells into mice with a genetic condition that resembles Tay-Sachs disease, Snyder and his colleagues found that the human cells traveled to the affected area of the brain and made neurons that pumped out the vital chemical missing in the disease. Further studies must be carried out to determine if the stem cell transplant helped the Tay-Sachs mice.

If all goes well, human trials with stem cells may begin within five years, probably with Alzheimer's patients, Snyder said.

Stem cells can be grown in unlimited numbers from a single source, and the hope is that they can be used to treat all types of mental disorders without incurring rejection problems, he said.

"The neural stem cell is a powerful new addition that really opens up whole new vistas," Snyder said.

"For now, the stem cells and brain cells talk to each other to heal things, and we don't even know what that language is. But we intend to learn it."